Substituted amides, their preparation and use

ABSTRACT

An amide of the formula Iand its tautomeric forms, possible enantiomeric and diastereomeric forms, E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings:A -(CH2)p-R&lt;1&gt;, where R&lt;1 &gt;can be pyrrolidine, morpholine, piperidine, -NR&lt;5&gt;R&lt;6 &gt;andand R&lt;5&gt;, R&lt;6 &gt;and R&lt;7 &gt;can, independently of one another, be hydrogen, C1-C4-alkyl, CH2Ph, Ph, CH2CH2Ph, it also being possible for the phenyl rings to be substituted by R&lt;6&gt;, and p can be 1 and 2, andB can be phenyl, pyridyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by up to 2 R&lt;8 &gt;radicals, andD can be a bond, -(CH2)m, -CH=CH-, -C=C-, andY is phenyl, pyridine, pyrimidine and pyrazine andn is a number 0, 1 or 2, andm,q are, independently of one another, a number 0, 1, 2, 3 or 4.

This application is a national phase application of PCT/EP 99/02633filed Apr. 20, 1999 which claims the priority of German patentapplication No. 19818615.0 filed Apr. 20, 1998.

The present invention relates to novel amides which are inhibitors ofenzymes, especially cysteine proteases such as calpain (=calciumdependant cysteine proteases) and its isoenzymes and cathepsins, forexample B and L.

Calpains are intracellular proteolytic enzymes from the group ofcysteine proteases and are found in many cells. Calpains are activatedby an increase in the calcium concentration, a distinction being madebetween calpain I or μ-calpain, which is activated by μ-molarconcentrations of calcium ions, and calpain II or m-calpain, which isactivated by m-molar concentrations of calcium ions (P. Johnson, Int. J.Biochem. 1990, 22(8), 811-22). Further calpain isoenzymes have now beenpostulated too (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995,376(9), 523-9).

It is suspected that calpains play an important part in variousphysiological processes. These include cleavages of regulatory proteinssuch as protein kinase C, cytoskeletal proteins such as MAP 2 andspectrin, muscle proteins, protein degradation in rheumatoid arthritis,proteins in the activation of platelets, neuropeptide metabolism,proteins in mitosis and others which are listed in M. J. Barrett et al.,Life Sci. 1991, 48, 1659-69 and K. K. Wang et al., Trends in Pharmacol.Sci., 1994, 15, 412-9.

Elevated calpain levels have been measured in various pathophysiologicalprocesses, for example: ischemias of the heart (e.g. myocardialinfarct), of the kidney or of the central nervous system (e.g. stroke),inflammations, muscular dystrophies, cataracts of the eyes, injuries tothe central nervous system (e.g. trauma), Alzheimer's disease etc. (seeK. K. Wang, above). It is suspected that there is a connection betweenthese disorders and elevated and persistent intracellular calciumlevels. This results in overactivation of calcium-dependent processes,which are then no longer subject to physiological control. Accordingly,overactivation of calpains may also induce pathophysiological processes.

It has therefore been postulated that inhibitors of calpain enzymes maybe useful for treating these disorders. Various investigations haveconfirmed this. Thus, Seung-Chyul Hong et al., Stroke 1994, 25(3), 663-9and R. T. Bartus et al., Neurological Res. 1995, 17, 249-58 have shown aneuroprotective effect of calpain inhibitors in acute neurodegenerativedisorders or ischemias like those occurring after stroke. Likewise,calpain inhibitors improved the recovery of the memory deficits andneuromotor disturbances occurring after experimental brain trauma (K. E.Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93, 3428-3433). C. L.Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6, found aprotective effect of calpain inhibitors on kidneys damaged by hypoxia.Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1), 40-8, were able toshow beneficial effects of calpain inhibitors after cardiac damageproduced by ischemia or reperfusion. Since the release of the β-AP4protein is inhibited by calpain inhibitors, a potential therapeutic usefor Alzheimer's disease has been proposed (J. Higaki et al., Neuron,1995, 14, 651-59). The release of interleukin-1α is likewise inhibitedby calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6(6),597-601). It has further been found that calpain inhibitors havecytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass.Breast Cancer Res., Sendai Jp, Sep. 25-28, 1994, Int. J. Oncol. 5(Suppl.), 1994, 381). Further possible uses of calpain inhibitors aredetailed in K. K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8.

Calpain inhibitors have already been described in the literature.However, these are predominantly either irreversible or peptideinhibitors. Irreversible inhibitors are usually alkylating substancesand have the disadvantage that they react nonselectively or are unstablein the body. Thus, these inhibitors often show unwanted side effectssuch as toxicity, and are accordingly of limited use or unusable. Theirreversible inhibitors can be said to include, for example, theepoxides E 64 (E. B. McGowan et al., Biochem. Biophys. Res. Commun.1989, 158, 432-5), α-halo ketones (H. Angliker et al., J. Med. Chem.1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lett. 1990,191-194).

Many known reversible inhibitors of cysteine proteases such as calpainare peptide aldehydes, in particular dipeptide and tripeptide aldehydessuch as, for example, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Trends in Biol.Sci. 1991, 16, 150-3). Under physiological conditions, peptide aldehydeshave the disadvantage that, owing to the high reactivity, they are oftenunstable, may be rapidly metabolized and are prone to nonspecificreactions which may cause toxic effects (J. A. Fehrentz and B. Castro,Synthesis 1983, 676-78).

JP 08183771 (CA 1996, 605307) and EP 520336 have described aldehydesderived from 4-piperidinoylamides [sic] and1-carbonyl-4-piperidinoylamides [sic] as calpain inhibitors. However,the aldehydes which are claimed herein and are derived from amides ofthe general structure I with heteroaromatic substituents have previouslybeen described [sic]

Peptide ketone derivatives are likewise inhibitors of cysteineproteases, in particular calpains. Thus, for example, ketone derivativeswhere the keto group is activated by an electron-attracting group suchas CF₃ are known to be inhibitors of serine proteases. In the case ofcysteine proteases, derivatives with ketones activated by CF₃ or similargroups have little or no activity (M. R. Angelastro et al., J. Med.Chem. 1990, 33, 11-13). Surprisingly, to date only ketone derivatives inwhich, on the one hand, leaving groups in the a position causeirreversible inhibition and, on the other hand, the keto group isactivated by a carboxylic acid derivative have been found to beeffective inhibitors of calpain (see M. R. Angelastro et al., see above;WO 92/11850; WO 92,12140; WO 94/00095 and WO 95/00535). However, onlypeptide derivatives of these keto amides and keto esters have to datebeen described as effective (Zhaozhao Li et al., J. Med. Chem. 1993, 36,3472-80; S. L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 and seeabove M. R. Angelastro et al.).

Ketobenzamides have already been described in the literature. Thus, theketo ester PhCO—Abu—COOCH₂CH₃ has been described in WO 91/09801, WO94/00095 and 92/11850. The analogous phenyl derivativePh—CONH—CH(CH₂Ph)—CO—COCOOCH₃ was, however, found to be only a weakcalpain inhibitor in M. R. Angelastro et al., J. Med. Chem. 1990, 33,11-13. This derivative is also described in J. P. Burkhardt, TetrahedronLett., 1988, 3433-36. The significance of the substituted benzamideshas, however, never been investigated to date.

In a number of therapies, such as for stroke, the active ingredients areadministered intravenously, for example as infusion solution. To do thisit is necessary to have available substances, in this case calpaininhibitors, which have adequate solubility in water so that an infusionsolution can be prepared. Many of the described calpain inhibitors have,however, the disadvantage that they have only low or no solubility inwater and thus are unsuitable for intravenous administration. Activeingredients of this type can be administered only with ancillarysubstances intended to confer solubility in water (cf. R. T. Bartus etal. J. Cereb. Blood Flow Metab. 1994, 14, 537-544). These ancillarysubstances, for example polyethylene glycol, often have side effects,however, or are even incompatible. A non-peptide calpain inhibitor whichis soluble in water without ancillary substances would thus be a greatadvantage. No such inhibitor has been described to date, and it wouldthus be novel.

Non-peptide aldehydes, keto carboxylic esters and keto amide derivativeswere described in the present invention. These compounds are novel andsurprisingly show the possibility of obtaining potent non-peptideinhibitors of cysteine proteases, such as, for example, calpain, byincorporating rigid structural fragments. In addition, all the presentcompounds of the general formula I have at least one aliphatic amineradical and are thus able to bind [sic] salts with acids. This resultsin improved solubility in water and thus the compounds show the requiredprofile for intravenous administration as is necessary, for example, forstroke therapy.

The present invention relates to amides which have heterocyclicsubstituents and the general formula I

and their tautomeric and isomeric forms, possible enantiomeric anddiastereomeric forms, and possible physiologically tolerated salts, inwhich the variables have the following meanings:

A —(CH₂)_(p)—R¹, where R¹ can be pyrrolidine [sic], morpholine [sic],hexahydroazepine [sic], piperidine [sic], —NR⁵R⁶ and

 it also being possible for the cyclic amines to be substituted by oneor two R¹⁵ radicals, and R¹⁵ are [sic] hydrogen, C₁-C₆-alkyl,O—C₁-C₆-alkyl and phenyl, and R⁵, R⁶ and R⁷ can be, independently of oneanother, hydrogen, C₁-C₄-alkyl, cyclohexyl, cyclopentyl, CH₂Ph, Ph,CH₂CH₂Ph, it also being possible for the phenyl rings to be substitutedby R⁶, and p can be 1 and 2, and

can be phenyl [sic], pyridyl [sic], pyrazyl [sic], pyrimidyl [sic] andpyridazyl [sic], it also being possible for the rings to be substitutedby up to 2 R⁸ radicals, and

A and B together can also be

 and R¹⁶ is hydrogen, C₁-C₆-alkyl and (CH₂)₁₋₄-phenyl, it also beingpossible for the phenyl ring to be substituted by a maximum of 2 R⁶radicals, and

D can be a bond, —(CH₂)₀₋₂—O—(CH₂)₀₋₂, —(CH₂)_(m)—, —CH═CH—, —C≡C—, and

R² is chlorine, bromine, fluorine, C₁-C₆-alkyl, NHCO—C₁-C₄-alkyl,NHSO₂—C₁-C₄-alkyl, NO₂, —O—C₁-C₄-alkyl and NH₂, and

R³ is —C₁-C₆-alkyl, branched or unbranched, and which may also carry aSCH₃ radical, a phenyl ring, imidazolyl ring, indolyl ring andcyclopentyl, cycloheptyl or cyclohexyl ring which is in turn substitutedby by [sic] a maximum of two R⁸ radicals, where R⁸ is hydrogen,C₁-C₄-alkyl, branched or unbranched, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I,CF₃, NO₂, NH₂, CN, COOH, COO—C₁-C₄-alkyl, NHCO—C₁-C₄-alkyl,—NHSO₂—C₁-C₄-alkyl and —SO₂—C₁-C₄-alkyl; and

Y is phenyl [sic], pyridine, pyridazine, pyrimidine and pyrazine and

R⁴ is hydrogen, COOR⁹ and CO—Z in which Z is NR¹⁰R¹¹ and

R⁹ is hydrogen, C₁-C₆-alkyl, linear or branched, and which may [lacuna]substituted by a phenyl ring which may itself also be substituted by oneor two R¹² radicals, and

R¹⁰ is hydrogen, C₁-C₆-alkyl, linear or branched, and which may [lacuna]substituted by a phenyl ring which itself may also be substituted by oneor two R¹² radicals, and

R¹ is hydrogen, C₁-C₆-alkyl, branched or unbranched, which may also beand [sic] substituted by a phenyl ring which may also carry an R⁹radical, and

R¹² can be hydrogen, C₁-C₄-alkyl, branched or unbranched,—O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN, COOH,COO—C₁-C₄-alkyl, —NHCO—C₁-C₄-alkyl, —NHCO-phenyl, —NHSO₂—C₁-C₄-alkyl,—NHSO₂-phenyl, —SO₂—C₁-C₄-alkyl and —SO₂-phenyl,

R¹³ is hydrogen, C₁-C₆-alkyl, linear or branched, and which may [lacuna]substituted by a phenyl ring which may itself also be substituted by oneor two R¹² radicals, and

R¹⁴ is hydrogen, C₁-C₆-alkyl, linear or branched, and which may [lacuna]substituted by a phenyl ring which may itself also be substituted by oneor two R¹² radicals, and

n is a number 0, 1 or 2, and

m, q is, independently of one another, a number 0, 1, 2, 3 or 4.

Preferred compounds of the general formula I are those in which

A —CH₂—R¹, where R¹ can be pyrrolidino, piperidino, —NR⁵R⁶ and

 and R⁵, R⁶ and R⁷ can be, independently of one another, hydrogen andC₁-C₄-alkyl, and

B phenyl [sic]

—CH═CH—

R² hydrogen

R³ benzyl, CH₂CH₂CH₂CH₃, CH₂CH₂CH₂CH₂CH₃ and

Y phenyl [sic] and pyridine and

R⁴ hydrogen and CO—NH₂ and

all the remaining variables have the same meaning as in claim 1.

The compounds of the formula I can be employed as racemates, asenantiomerically pure compounds or as diastereomers. If enantiomericallypure compounds are required, these can be obtained, for example, bycarrying out a classical racemate resolution with the compounds of theformula I or their intermediates using a suitable optically active baseor acid. On the other hand, the enantiomeric compounds can likewise beprepared by using commercially purchasable compounds, for exampleoptically active amino acids such as phenylalanine, tryptophan andtyrosine.

The invention also relates to compounds which are mesomers or tautomersof compounds of the formula I, for example those in which the aldehydeor keto group in formula I is in the form of an enol tautomer.

The invention further relates to the physiologically tolerated salts ofthe compounds I which can be obtained by reacting compounds I with asuitable acid or base. Suitable acids and bases are listed, for example,in Fortschritte der Arzneimittelforschung, 1966, Birkhäuser Verlag, Vol.10, pp. 224-285. These include, for example, hydrochloric acid, citricacid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid,acetic acid, formic acid, maleic acid, fumaric acid etc., and sodiumhydroxide, lithium hydroxide, potassium hydroxide and tris.

Amides I according to the invention with an aldehyde group can beprepared in various ways, as outlined in synthesis scheme 1.

Heterocyclic carboxylic acids II are linked to suitable amino alcoholsIII to give the corresponding amides IV. Conventional peptide couplingmethods are used for this, as detailed either in C. R. Larock,Comprenhensive [sic] Organic Transformations, VCH Publisher, 1989, page972 et seq., or in Houben-Weyl, Methoden der organischen Chemie, 4thedition, E5, Chapter V. It is preferred to use “activated” acidderivatives of II, with the acid group COOH being converted into a groupCOL. L is a leaving group such as, for example, Cl, imidazole andN-hydroxybenzotriazole. This activated acid is then reacted with aminesto give the amides IV. The reaction takes place in anhydrous inertsolvents such as methylene chloride, tetrahydrofuran anddimethylformamide at temperatures from −20 to +25° C. These alcoholderivatives IV can be oxidized to the aldehyde derivatives I accordingto the invention. Various conventional oxidation reactions can be usedfor this (see C. R. Larock, Comprenhensive [sic] OrganicTransformations, VCH Publisher, 1989, page 604 et seq.) such as, forexample, Swern and Swern-analogous oxidations (T. T. Tidwell, Synthesis,1990, 857-70), sodium hypochloride [sic]/TEMPO (S. L. Harbenson et al.,see above) or Dess-Martin (J. Org. Chem. 1983, 48, 4155). Preferablyused for this are inert aprotic solvents such as dimethylformamide,tetrahydrofuran or methylene chloride with oxidizing agents such asDMSO/py×SO₃ or DMSO/oxalyl chloride at temperatures from −50 to +25° C.,depending on the method (see above literature).

Alternatively, the carboxylic acid II can be reacted with aminohydroxamic acid derivatives VI to give benzamides VII. The reaction inthis case is carried out in the same way as for preparing IV. Thehydroxamic derivatives VI can be obtained from the protected amino acidsV by reaction with a hydroxylamine. An amide preparation process alreadydescribed is also used in this case. Elimination of the protective groupX, for example Boc, takes place in a normal way, for example withtrifluoroacetic acid. The amide hydroxamic acids VII obtained in thisway can be converted by reduction into the aldehydes I according to theinvention. The reducing agent used for this is, for example, lithiumaluminum hydride at temperatures from −60 to 0° C. in inert solventssuch as tetrahydrofuran or ether. Carboxylic acids or acid derivativessuch as esters IX (P=COOR′, COSR′) can also be prepared in analogy tothe last process and can likewise be converted by reduction into thealdehydes I according to the invention. These processes are listed in R.C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989,pages 619-26.

The amides I according to the invention, which have heterocyclicsubstituents and have a keto amide or keto ester group, can be preparedin various ways which have been outlined in synthesis schemes 2 and 3.

The carboxylic esters IIa are converted where appropriate with acids orbases such as lithium hydroxide, sodium hydroxide or potassium hydroxidein aqueous medium or in mixtures of water and organic solvents such asalcohols or tetrahydrofuran at room temperature or elevatedtemperatures, such as 25-100° C., into the acids II.

These acids II are linked to an α-amino acid derivative using customaryconditions which are listed, for example, in Houben-Weyl, Methoden derorganischen Chemie, 4th edition, E5, Chapter V, and C. R. Larock,Comprehensive Organic Transformations, VCH Publisher, 1989, Ch. 9.

For example, the carboxylic acids II are converted into the “activated”acid derivatives IIb (COOH→COL), where L is a leaving group such as Cl,imidazole and N-hydroxybenzotriazole, and then converted into thederivative XI by adding an amino acid derivative H₂N—CH(R³)—COOR. Thisreaction takes place in anhydrous inert solvents such as methylenechloride, tetrahydrofuran and dimethylformamide at temperatures from −20to +25° C.

The derivatives XI, which are usually esters, are converted into theketo carboxylic acids XII by hydrolysis analogous to that describedabove. The keto esters I′ are prepared in a Dakin-West-analogousreaction using a method of Zhaozhao Li et al., J. Med. Chem., 1993, 36,3472-80. This entails a [sic] carboxylic acids such as XII being reactedwith oxalic monoester chloride at elevated temperature (50-100° C.) insolvents such as, for example, tetrahydrofuran, and the product obtainedin this way then being reacted with bases such as sodium ethanolate inethanol at temperatures of 25-80° C. to give the keto ester I′ accordingto the invention. The keto esters I′ can be hydrolyzed as describedabove for example to keto carboxylic acids according to the invention.

The reaction to give keto benzamides I′ likewise takes place in analogyto the method of ZhaoZhao Li et al. (see above). The keto group in I′ isprotected by adding 1,2-ethanedithiol with Lewis acid catalysis, suchas, for example, boron trifluoride etherate, in inert solvents such asmethylene chloride at room temperature, resulting in a dithiane. Thesederivatives are reacted with amines R³—H in polar solvents such asalcohols at temperatures of 0-80° C., resulting in the keto amides I(R⁴=Z or NR¹⁰R¹¹).

An alternative method is depicted in scheme 3. The keto carboxylic acidsII are reacted with amino hydroxy carboxylic acid derivatives XIII (forpreparation of XIII, see S. L. Harbenson et al., J. Med. Chem. 1994, 37,2918-29 or J. P. Burkhardt et al. Tetrahedron Lett. 1988, 29, 3433-3436)using customary peptide coupling methods (see above, Houben-Weyl),resulting in amides XIV. These alcohol derivatives XIV can be oxidizedto the keto carboxylic acid derivatives I according to the invention. Itis possible to use for this various customary oxidation reactions (seeC. R. Larock, Comprehensive Organic Transformations, VCH Publisher,1989, page 604 et seq.) such as, for example, Swern and Swern-analogousoxidations, preferably dimethyl sulfoxide/pyridine-sulfur trioxidecomplex in solvents such as methylene chloride or tetrahydrofuran, whereappropriate with the addition of dimethyl sulfoxide, at room temperatureor temperatures from −50 to 25° C. (T. T. Tidwell, Synthesis 1990,857-70) or sodium hypochloride [sic]/TEMPO (S. L. Harbenson et al., seeabove).

In the case of α-hydroxy esters XIV (X=O-alkyl), these can be hydrolyzedto carboxylic acids XV using methods analogous to those above, butpreferably using lithium hydroxide in water/tetrahydrofuran mixtures atroom temperature. Other esters or amides XVI are prepared by reactionwith alcohols or amines under coupling conditions described above. Thealcohol derivative XVI can be oxidized to give keto carboxylic acidderivatives I according to the invention.

The preparation of the carboxylic esters II have [sic] already beendescribed for some instances, or it takes place by usual chemicalmethods.

Compounds in which C is a bond are prepared by conventional aromaticcoupling, for example Suzuki coupling with boric acid derivatives andhalides with palladium catalysis or copper-catalyzed coupling ofaromatic halides. The alkyl-bridged radicals (C═—(CH₂)_(m)—) can beprepared by reducing the analogous ketones or by alkylating theorganolithium, e.g. ortho-phenyloxazolidines, or other organometalliccompounds (cf. I. M. Dordor et al., J. Chem. Soc. Perkins Trans. I,1984, 1247-52).

Ether-bridged derivatives are prepared by alkylating the correspondingalcohols or phenols with halides. Alkene- and alkyne-bridged compoundsare prepared, for example, by the Heck reaction from aromatic halidesand corresponding alkenes and alkynes (cf. I. Sakamoto et al., Chem.Pharm. Bull., 1986, 34, 2754-59).

The amides I with heterocyclic substituents of the present invention areinhibitors of cysteine proteases, especially cysteine proteases such ascalpains I and II and cathepsins B and L.

The inhibitory effect of the amides I with heterocyclic substituents hasbeen determined using enzyme assays known from the literature,determining as criterion of effect a concentration of the inhibitor atwhich 50% of the enzyme activity is inhibited (=IC₅₀). The amides I weremeasured in this way for their inhibitory effect on calpain I, calpainII and cathepsin B.

Cathepsin B Assay

The inhibition of cathepsin B was determined by a method analogous tothat of S. Hasnain et al., J. Biol. Chem., 1993, 268, 235-40.

2 μl of an inhibitor solution prepared from inhibitor and DMSO (finalconcentrations: 100 μM to 0.01 μM) are [lacuna] to 88 μl of cathepsin B(cathepsin B from human liver (Calbiochem), diluted to 5 units in 500 μMbuffer). This mixture is preincubated at room temperature (25° C.) for60 minutes and then the reaction is started by adding 10 μl of 10 mMZ-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is followed in amicrotiter plate reader at 405 nM [sic] for 30 minutes. The IC₅₀s arethen determined from the maximum gradients.

Calpain I and II Assay

The testing of the inhibitory properties of calpain inhibitors takesplace in buffer with 50 mM tris-HCl, pH 7.5; 0.1 M NaCl; 1 mMdithiotreithol [sic]; 0.11 mM CaCl₂, using the fluorogenic calpainsubstrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem/Switzerland).Human μ-calpain is isolated from erythrocytes, and enzyme with apurity>95%, assessed by SDS-PAGE, Western blot analysis and N-terminalsequencing, is obtained after more [sic] chromatographic steps(DEAE-Sepharose, phenyl-Sepharose, Superdex 200 and blue Sepharose). Thefluorescence of the cleavage product 7-amino-4-methylcoumarin (AMC) isfollowed in a Spex Fluorolog fluorimeter at λex=380 nm and λem=460 nm.The cleavage of the substrate is linear in a measurement range of 60min., and the autocatalytic activity of calpain is low, if the tests arecarried out at temperatures of 12° C. The inhibitors and the calpainsubstrate are added to the test mixture as DMSO solutions, and the finalconcentration of DMSO ought not to exceed 2%.

In a test mixture, 10 μl of substrate (250 μM final) and then 10 μl ofμ-calpain (2 μg/ml final, i.e. 18 nM) are added to a 1 ml cuvettecontaining buffer. The calpain-mediated cleavage of the substrate ismeasured for 15 to 20 min. Then 10 μl of inhibitor (50 to 100 μMsolution in DMSO) are added and the inhibition of cleavage is measuredfor a further 40 min.

K_(i) values are determined using the classical equation for reversibleinhibition:

Ki=I (v0/vi)−1; where I=inhibitor concentration, v0=initial rate beforeaddition of the inhibitor; vi=reaction rate at equilibrium.

The rate is calculated from v=AMC liberation/time, i.e. height/time.

Calpain is an intracellular cysteine protease. Calpain inhibitors mustpass through the cell membrane in order to prevent intracellularproteins being broken down by calpain. Some known calpain inhibitors,such as, for example, E 64 and leupeptin, cross cell membranes onlypoorly and accordingly show only a poor effect on cells, although theyare good calpain inhibitors. The aim is to find compounds better able tocross membranes. Human platelets are used to demonstrate the ability ofcalpain inhibitors to cross membranes.

Calpain-mediated Breakdown of Tyrosine Kinase pp60src in Platelets

Tyrosine kinase pp60src is cleaved by calpain after activation ofplatelets. This has been investigated in detail by Oda et al. in J.Biol. Chem., 1993, 268, 12603-12608. This revealed that the cleavage ofpp60src can be prevented by calpeptin, a calpain inhibitor. The cellularefficacy of our substances was tested based on this publication. Fresh,citrated, human blood was centrifuged at 200 g for 15 min. Theplatelet-rich plasma was pooled and diluted 1:1 with platelet buffer(platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM MgCl₂×6 H₂O, 0.24 mMNaH₂PO₄×H₂O, 12 mM NaHCO₃, 5.6 mM glucose, 1 mM EDTA, pH 7.4). After acentrifugation step and washing step with platelet buffer, the plateletswere adjusted to 10⁷ cells/ml. The human platelets were isolated at RT.

In the assay mixture, isolated platelets (2×10⁶) were preincubated withvarious concentrations of inhibitors (dissolved in DMSO) at 37° C. for 5min. The platelets were then activated with 1 μM ionophore A23187 and 5mM CaCl₂. After incubation for 5 min., the platelets were brieflycentrifuged at 13000 rpm, and the pellet was taken up in SDS samplebuffer (SDS sample buffer: 20 mM tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mMDTT, 0.5 mM PMSF, 5 μg/ml leupeptin, 10 μg/ml pepstatin, 10% glyceroland 1% SDS). The proteins were fractionated in a 12% gel, and pp60srcand its 52 kDa and 47 kDa cleavage products were identified by Westernblotting. The polyclonal rabbit antibody used, anti-Cys-src(pp60^(c-rc)) was purchased from Biomol Feinchemikalien (Hamburg). Thisprimary antibody was detected using a second, HRP-coupled goat antibody(Boehringer Mannheim, FRG). The Western blotting was carried out byknown methods. The cleavage of pp60src was quantified by densitometry,using as controls unactivated (control 1: no cleavage) and ionophore-and calcium-treated platelets (control 2: corresponds to 100% cleavage).The ED₅₀ corresponds to the concentration of inhibitor at which theintensity of the color reaction is reduced by 50%.

Glutamate-induced Cell Death in Cortical Neurones

The test was carried out as in Choi D. W., Maulucci-Gedde M. A. andKriegstein A. R., “Glutamate neurotoxicity in cortical cell culture”. J.Neurosci. 1989 [sic], 7, 357-368. The cortex halves were dissected outof 15-day old mouse embryos and the single cells were obtainedenzymatically (trypsin). These cells (glia and cortical neurones) areseeded out in 24-well plates. After three days (laminin-coated plates)or seven days (ornithine-coated plates), the mitosis treatment iscarried out with FDU (5-fluoro-2-deoxyuridines). 15 days afterpreparation of the cells, cell death is induced by adding glutamate (15minutes). After removal of glutamate, the calpain inhibitors are added.24 hours later, the cell damage is estimated by determining lactatedehydrogenase (LDH) in the cell culture supernatant.

It is postulated that calpain is also involved in apoptotic cell death(M. K. T. Squier et al., J. Cell. Physiol. 1994, 159, 229-237; T. Patelet al. Faseb Journal 1996, 590, 587-597).

For this reason, in another model, cell death was induced in a humancell line with calcium in the presence of a calcium ionophore. Calpaininhibitors must get inside the cell and inhibit calpain there in orderto prevent the induced cell death.

Calcium-mediated Cell Death in NT2 Cells

Cell death can be induced in the human cell line NT2 by calcium in thepresence of the ionophore A 23187. 10⁵ cells/well were plated out inmicrotiter plates 20 hours before the test. After this period, the cellswere incubated with various concentrations of inhibitors in the presenceof 2.5 μM ionophore and 5 mM calcium. 0.05 ml of XTT (Cell ProliferationKit II, Boehringer Mannheim) was added to the reaction mixture after 5hours. The optical density is determined approximately 17 hours later,in accordance with the manufacturer's information, in an SLT Easy ReaderEAR 400. The optical density at which half the cells have died iscalculated from the two controls with cells without inhibitors incubatedin the absence and presence of ionophore.

Elevated glutamate activities occur in a number of neurologicaldisorders or psychological disturbances and lead to states ofoverexcitation or toxic effects in the central nervous system (CNS). Theeffects of glutamate are mediated by various receptors. Two of thesereceptors are classified, in accordance with the specific agonists, asNMDA receptor and AMPA receptor. Antagonists to these glutamate-mediatedeffects can thus be employed for treating these disorders, in particularfor therapeutic use for neurodegenerative disorders such as Huntington'schorea and Parkinson's disease, neurotoxic impairments after hypoxia,anoxia, ischemia and after lesions like those occurring after stroke andtrauma, or else as antiepileptics (cf. Arzneim. Forschung 1990, 40,511-514; TIPS, 1990, 11, 334-338; Drugs of the Future 1989, 14,1059-1071).

Protection From Cerebral Overexcitation by Excitatory Amino Acids (NMDAand AMPA Antagonism in Mice)

Intracerebral administration of excitatory amino acids (EAA) inducessuch drastic overexcitation that it leads to convulsions and death ofthe animals (mice) within a short time. These signs can be inhibited bysystemic, e.g. intraperitoneal, administration of centrally actingsubstances (EAA antagonists). Since excessive activation of EAAreceptors in the central nervous system plays a significant part in thepathogenesis of various neurological disorders, it is possible to inferfrom the detected EAA antagonism in vivo that the substances may havetherapeutic uses for such CNS disorders. As a measure of the efficacy ofthe substances, an ED₅₀ was determined, at which 50% of the animals arefree of signs, owing to the previous i.p. administration of the measuredsubstance, by a fixed dose of either NMDA or AMPA.

The amides I with heterocyclic substituents are inhibitors of cysteinederivatives [sic] like calpain I and II and cathepsin B and L, and canthus be used to control diseases associated with an elevated activity ofcalpain enzymes or cathepsin enzymes. The present amides I canaccordingly be used to treat neurodegenerative disorders occurring afterischemia, damage due to reperfusion after vascular occlusions, trauma,subarachnoid hemorrhages and stroke, and neurodegenerative disorderssuch as multi-infarct dementia, Alzheimer's disease, Huntington'sdisease and epilepsies and, in addition, to treat damage to the heartafter cardiac ischemias, damage to the kidneys after renal ischemia,skeletal muscle damage, muscular dystrophies, damage caused byproliferation of smooth muscle cells, coronary vasospasms, cerebralvasospasms, cataracts of the eyes, restenosis of the blood vessels afterangioplasty. In addition, the amides I may be useful in the chemotherapyof tumors and metastasis thereof and for treating disorders in which anelevated interleukin-1 level occurs, such as inflammation and rheumaticdisorders.

The pharmaceutical preparations according to the invention comprise atherapeutically effective amount of the compounds I in addition toconventional pharmaceutical ancillary substances.

The active ingredients can be present in the usual concentrations forlocal external use, for example in dusting powders, ointments or sprays.As a rule, the active ingredients are present in an amount of from 0.001to 1% by weight, preferably 0.001 to 0.1% by weight.

For internal use, the preparations are administered in single doses.From 0.1 to 100 mg are given per kg of body weight in a single dose. Thepreparation may be administered in one or more doses each day, dependingon the nature and severity of the disorders.

The pharmaceutical preparations according to the invention comprise,apart from the active ingredient, the customary excipients and diluentsappropriate for the required mode of administration. For local externaluse it is possible to use pharmaceutical ancillary substances such asethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenatedcastor oil, polyacrylic acid, polyethylene glycol, polyethylene glycolstearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum andwool fat. Suitable examples for internal use are lactose, propyleneglycol, ethanol, starch, talc and polyvinylpyrrolidone.

It is also possible for antioxidants such as tocopherol and butylatedhydroxyanisole, and butylated hydroxytoluene, flavor-improvingadditives, stabilizers, emulsifiers and lubricants to be present.

The substances which are present in the preparation in addition to theactive ingredient, and the substances used in producing thepharmaceutical preparations, are toxicologically acceptable andcompatible with the active ingredient in each case. The pharmaceuticalpreparations are produced in a conventional way, for example by mixingthe active ingredient with other customary excipients and diluents.

The pharmaceutical preparations can be administered in various ways, forexample orally, parenterally, such as intravenously by infusion,subcutaneously, intraperitoneally and topically. Thus, possiblepresentations are tablets, emulsions, solutions for infusion andinjection, pastes, ointments, gels, creams, lotions, dusting powders andsprays.

EXAMPLES Example 1(S)-2-(E-2-(4-(N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide[sic]

a) Ethyl 2-(E-2-(4-(N,N-dimethylaminomethyl)phenyl)ethen-1-yl)benzoate

18.8 g (82 mmol) of ethyl 2-bromobenzoate, 17.2 g (10⁷ mmol) of4-(N,N,-dimethylaminomethyl)styrene [sic], 20.7 g (205 mmol) oftriethylamine, 0.36 g of palladium(II) acetate and 0.96 g oftri(o-tolyl)phosphine were mixed in 200 ml of dimethylformamide and,after addition of 1 ml of water, stirred at 140° C. for 3 h. Thereaction mixture was then concentrated in vacuo, and the resultingresidue was partitioned between ethyl acetate and water. The organicphase was separated off, washed with water, dried and concentrated invacuo. The residue was then recrystallized from petroleum ether. 16.1 g(63%) of the product were obtained.

b) 2-(E-2-(4-(N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-benzoic acid

15.5 g (50 mmol) of the intermediate 1a were dissolved in 150 ml ofethanol, and 50 ml of 2M sodium hydroxide solution were added. Themixture was stirred at room temperature for 16 h. The solution was thenneutralized with 2M hydrochloric acid, and the ethanol was removed invacuo. The resulting precipitate was filtered off with suction anddried. 13.6 g (97%) of the product were obtained.

c)(S)-2-(E-2-(4-(N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)benzamide[sic]

1.97 g (7 mmol) of the intermediate 1b and 1.06 g (7 mmol) of(S)-phenylalaninol were mixed in 25 ml of methylene chloride, and 1.77 g(17.5 mmol) of triethylamine and 0.95 g (7 mmol) of1-hydroxybenzotriazole were added. Then, at 0° C., 1.34 g (7 mmol) of1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride were added,and the mixture was stirred at 0° C. for 1 h and then at roomtemperature for 16 h. The reaction mixture was washed successively with100 ml of 5% strength citric acid and 100 ml of sodium bicarbonatesolution and, after drying, concentrated in vacuo. 2.63 g (88%) of theproduct were obtained.

d)(S)-2-(E-2-(4-N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)benzamide[sic]

2.40 g (5.6 mmol) of intermediate 1c and 2.27 g (22.4 mmol) oftriethylamine were dissolved in 25 ml of dry dimethyl sulfoxide, and3.57 g (22.4 mmol) of pyridine/sulfur trioxide complex were added. Themixture was stirred at room temperature for 16 h. The mixture was thenadded to aqueous sodium bicarbonate solution, and the precipitate wasfiltered off with suction. The aqueous phase was extracted with ethylacetate, which was then dried and concentrated in vacuo. This residuewas combined with the first precipitate. 1.57 g (68%) of the productwere obtained.

¹H-NMR (D₆-DMSO): δ=2.4 (6H), 2.8-3.1 (2H), 3.8 (1H), 7.0-7.7 (14H), 7.8(1H), 8.8 (1H) and 9.75 (1H) ppm.

Example 2(S)-2-(E-2-(4-(N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl)nicotinamide[sic]

a) Ethyl 2-(E-2-(4-(N,N-dimethylaminomethyl)phenyl)ethen-1-yl)nicotinate

6.7 g (39 mmol) of ethyl 2-chloronicotinate, 8.2 g (51 mmol) of4-(N,N-dimethylaminomethyl)styrene, 9.9 g (98 mmol) of triethylamine,0.36 g of palladium(II) acetate and 0.96 [lacuna] oftri(o-tolyl)phosphine were mixed in 150 ml of dimethylformamide and,after addition of 1 ml of water, stirred at 140° C. for 13 h. Thereaction mixture was then concentrated in vacuo, and the resultingresidue was partitioned between ethyl acetate and water. The organicphase was separated off, washed with water, dried and concentrated invacuo. The residue was then crystallized as oxalate from isopropanolafter addition of an equivalent amount of oxalic acid. 4.1 g (27%) ofthe product were obtained as monooxalate.

b) 2-(E-2-(4-N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-nicotinic acid

3.9 g (10 mmol) of the intermediate 2a were added to 100 ml ofethanol/tetrahydrofuran (1/1), and 25 ml of 2M sodium hydroxide solutionwere added. The mixture was stirred at room temperature for 16 h. Thereaction solution was then neutralized with 2M hydrochloric acid, andthe ethanol was removed in vacuo. The resulting precipitate was filteredoff with suction and dried. 2.46 g (87%) of the product were obtained.

c)(S)-2-(E-2-(4-N,N-Dimethylaminomethyl)phenyl)ethen-1-yl)-N-(3-phenylpropan-1-ol-2-yl)nicotinmide[sic]

2.03 g (7.2 mmol) of the intermediate 2b and 1.09 g (7.2 mmol) of(S)-phenylalaninol were added to 25 ml of methylene chloride, and 1.82 g(18 mmol) of triethylamine and 0.97 g (7.2 mmol) of1-hydroxybenzotriazole were added. Then, at 0° C., 1.38 g (7.2 mmol) of1-ethyl-3-(dimethylaminopropyl)-carbodiimide hydrochloride were added,and the mixture was stirred at 0° C. for 1 h and then at roomtemperature for 16 h. The reaction mixture was washed successively with100 ml of 5% strength citric acid and 100 ml of sodium bicarbonatesolution and, after drying, concentrated in vacuo. 2.45 g (82%) of theproduct were obtained.

d)(S)-2-(E-2-(4-N,N-Dimethylaminomethyl)phenyl)-ethen-1-yl)-N-(3-phenylpropan-1-al-2-yl))nicotinamide[sic]

2.27 g (5.5 mmol) of the intermediate 2c and 2.21 g (21.85 mmol) oftriethylamine were dissolved in 25 ml of dry dimethyl sulfoxide, and3.48 g (21.85 mmol) of pyridine/sulfur trioxide complex were added. Themixture was stirred at room temperature for 16 h. The reaction mixturewas then added to aqueous sodium bicarbonate solution, and theprecipitate was filtered off with suction. The aqueous phase wasextracted with ethyl acetate, which was then dried and concentrated invacuo. This residue was combined with the first precipitate. 1.4 g (61%)of the product were obtained.

¹H-NMR (D₆-DMSO): δ=2.15 (6H), 2.8 (1H), 3.3 (1H), 4.7 (1H), 6.9-7.8(13H), 8.6 (1H), 9.0 (1H) and 9.7 (1H) ppm.

Example 3N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(morpholin-1-ylmethyl)phenyl)ethen-1-yl)benzamide[sic]

a) N-(4-Vinylphenyl)methylmorpholine

20 ml (0.14 mol) of 4-vinylbenzylchloride and 25 ml (0.28 mol) ofmorpholine were refluxed in 150 ml of methanol for 3 h. The mixture wasthen concentrated in vacuo, and the resulting residue was partitionedbetween 1M hydrochloric acid and water [sic]. The acidic phase waswashed with ether and then made alkaline with 2M sodium hydroxidesolution. This aqueous phase was extracted with ether. This organicphase was dried and concentrated in vacuo, resulting in 24.6 g of theproduct.

b) Ethyl E-2-(4-(morpholin-1-ylmethyl)phenyl)ethen-1-ylbenzoate [sic]

14 g (68.9 mmol) of the intermediate 3a, 16.6 g (72.3 mmol) of ethyl2-bromobenzoate, 24 ml (172 mmol) of triethylamine, 0.36 g ofpalladium(II) chloride, 0.96 g of tri-o-tolylphosphine and 1 ml of waterwere heated in 150 ml of dimethylformamide at 100° C. for 2 h. Themixture was then poured into water and the resulting solution wasextracted with diethyl ether. The organic phase was dried and thenconcentrated in vacuo, resulting in 28 g of the product.

c) E-2-(4-(Morpholin-1-ylmethyl)phenyl)ethen-1-ylbenzoic acid xhydrochloride [sic]

28 g (80 mmol) of the intermediate 3b were dissolved [lacuna] 250 ml ofethanol, and 9 g (159 mmol) of potassium hydroxide dissolved in 150 mlof water were added. The mixture was stirred at room temperature for 16h. The mixture was then neutralized with hydrochloric acid and extractedwith ethyl acetate. The organic phase was dried and concentrated invacuo. The residue was dissolved in ethanol, and the hydrochloride wasprecipitated by adding ethanolic hydrogen chloride solution and was thenfiltered off with suction. 24.3 g of the product were obtained.

d)N-(1-Carbamoyl-1-hydroxy-3-phenylpropan-2-yl)-2-(E-2-(4-(morpholin-1-ylmethyl)phenyl)ethen-1-yl)benzamide[sic]

1 g (2.8 mmol) of the intermediate 3c were reacted in analogy to method2c with 3-amino-2-hydroxy-4-phenylbutyramide (J. P. Burkhardt et al.,Tetrahedon [sic] Lett. 1988, 3433-3436), resulting in 0.97 g of theproduct.

e)N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(morpholin-1-ylmethyl)phenyl)ethen-1-yl)benzamide[sic]

0.9 g (1.8 mmol) of intermediate 3d and 1 μL (7.2 mmol) of triethylaminewere dissolved in 20 ml of anhydrous dimethyl sulfoxide. Then, at roomtemperature, 0.57 g (3.6 mmol) of pyridine/sulfur trioxide complexdissolved in 12 ml of anhydrous dimethyl sulfoxide was added dropwise.The mixture was stirred for 30 minutes. The mixture was then poured intowater and neutralized with aqueous sodium bicarbonate solution. Theaqueous phase was extracted with ethyl acetate. The organic phase wasthen dried and concentrated in vacuo. The residue was precipitated fromacetone/ether, with 0.51 g of the product precipitating.

¹H-NMR (D₆-DMSO): δ=2.3 (4H), 2.9 (1H), 3.25 (1H), 3.5 (2H), 3.6 (2H),5.3 (1H), 7.0-7.6 (13H), 7.8 (2H), 8.1 (1H) and 8.9 (1H) ppm.

The following examples were prepared in analogy to the above examplesand methods:

Example 4N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(1-pyrrolidinylmethyl)phenyl)ethen-1-yl)benzamide[sic]

¹H-NMR (CF₃COOH): δ=2.15 (6H), 2.8 (2H), 3.3 (1H), 4.7 (1H), 6.9-7.8(13H), 8.6 (1H), 9.0 (1H) and 9.7 (1H) ppm.

Example 5N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(N,N-diethylaminomethyl)phenyl)ethen-1-yl)benzamide[sic]

¹H-NMR (D₆-DMSO): δ=1.0 (6H), 2.5 (4H), 2.9 (1H), 3.25 (1H), 3.5 (2H),5.4 (1H), 7.1-7.6 (13H), 7.8-7.9 (2H), 9.1 (1H) and 8.9 (1H) ppm.

Example 62-(2E-(4-(N,N-Benzylmethylaminomethyl)phenyl)ethen-1-yl)-N-(1-carbamoyl-1-oxo-3-phenylpropan-2-yl)benzamide[sic]

¹H-NMR (D₆-DMSO): δ=2.1 (3H), 2.9 (1H), 3.1-3.6 (5H), 5.3 (1H), 7.0-8.0(16H), 8.1 (1H) and 8.9 (1H) ppm.

Example 7N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(N,N-dimethylaminomethyl)phenyl)ethen-1-yl)benzamide[sic]

¹H-NMR (D₆-DMSO): δ=2.5 (6H), 2.9 (1H), 3.3 (1H), 3.9 (2H); 5.4 (1H),7.2-7.6 (15H), 8.9 (1H) and 8.9 (1H) ppm.

Example 8N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(N,N-di-n-propylaminomethyl)phenyl)ethen-1-yl)benzamide[sic]

¹H-NMR (D₆-DMSO): δ=0.8 (6H); 1.5 (4H); 2.3 (2H); 2.9 (1H); 3.25 (1H);3.5 (2H); 5.3 (1H), 7.1-7.5 (13H), 7.8 (2H), 8.1 (1H) and 8.9 (1H) ppm.

Example 9N-(1-Carbamoyl-1-oxohexan-2-yl)-2-(E-2-(4-(N,N-dimethylaminomethyl)phenyl)ethen-1-yl)benzamide[sic]hydrochloride

¹H-NMR (D₆-DMSO): δ=0.8 (3H); 1.2-1.9 (6H); 2.7 (6H), 4.2 (2H), 5.1(1H), 7.1-8.0 (11H), 8.05 (1H) and 8.8 (1H) ppm.

Example 10N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(4-methyl-1-piperazin-1-ylmethyl)phenyl)ethen-1-yl)benzamidex dihydrochloride [sic]

¹H-NMR (D₆-DMSO): δ=2.8-2.9 (3H), 3.1-3.8 (9H), 4.2 (2H), 5.3 (1H),7.1-7.9 (17H), 8.1 (1H) and 8.9 (1H) ppm.

Example 11N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(2-(N,N-dimethylaminomethyl)phenyl)ethen-1-yl)benzamide[sic]

¹H-NMR (D₆-DMSO): δ=2.1 (6H), 2.9 (1H), 3.2 (1H), 3.5 (1H); 5.3 (1H),7.0-8.0 (16H), 8.1 (1H) and 8.9 (1H) ppm.

Example 12N-(1-Carbamoyl-1-oxo-3-phenylpropan-2-yl)-2-(E-2-(4-(N,N,-dimethylaminomethyl)phenyl)ethen-1-yl)nicotinamide[sic]

¹H-NMR (D₆-DMSO): δ=2.3 (6H), 2.85 (1H), 3.2 (1H), 3.7 (1H); 5.4 (1H),7.2-7.6 (13H), 7.8 (1H), 8.6 (1H) and 9.15 (1H) ppm.

Example R′ R′′ R′′′

13 CONH₂ CH₂Ph

14 CONH₂ CH₂Ph

15 CONH₂ CH₂Ph

16 CONH₂ (CH₂)₃—CH₃

17 H CH₂Ph

18 CONH₂ CH₂Ph

19 CONH₂ CH₂Ph

20 CONH₂ CH₂Ph

21 CONH₂ (CH₂)₃CH₃

22 H CH₂Ph

23 CONH₂ CH₂Ph

24 H CH₂Ph

25 CONH₂ (CH₂)₃CH₃

26 H CH₂Ph

27 H CH₂Ph

28 CONH₂ CH₂Ph

29 CONH₂ CH₂Ph

30 CONH₂ (CH₂)₃CH₃

31 H CH₂Ph

32 CONH₂ CH₂Ph

33 CONH₂ CH₂Ph

34 H CH₂Ph

35 CONH₂ CH₂Ph

36 H CH₂Ph

37 CONH₂ CH₂Ph

38 H CH₂Ph

39 CONH₂ CH₂Ph

40 H CH₂Ph

41 CONH₂ CH₂Ph

42 H CH₂Ph

43 CONH₂ CH₂Ph

44 CONH₂ (CH₂)₃CH₃

45 H (CH₂)₃CH₃

46 CONH₂ (CH₂)₃CH₃

47 H (CH₂)₃CH₃

48 H CH₂Ph

49 H CH₂Ph

50 H CH₂Ph

51 H (CH₂)₃CH₃

52 CONH₂ (CH₂)₃CH₃

53 H CH₂Ph

54 H (CH₂)₃CH₃

55 CONH₂ (CH₂)₃CH₃

56 CONHCH₂CH₃ CH₂Ph

57 CONHCH₂CH₃ CH₂Ph

58 CONHCH₂CH₃ CH₂Ph

59 CONHCH₂CH₃ CH₂Ph

60 CONH₂ CH₂Ph

61 H CH₂Ph

62 H (CH₂)₃CH₃

63 CONH₂ (CH₂)₃CH₃

64 CONH₂ CH₂Ph

65 H CH₂Ph

66 H CH₂Ph

67 CONH₂ CH₂Ph

68 H (CH₂)₃CH₃

69 CONH₂ (CH₂)₃CH₃

70 H CH₂Ph

71 CONH₂ CH₂Ph

72 H CH₂Ph

73 CONH₂ CH₂Ph

74 H (CH₂)₃CH₃

75 CONH₂ (CH₂)₃CH₃

76 H (CH₂)₃CH₃

77 CONH₂ (CH₂)₃CH₃

78 H CH₂Ph

79 CONH₂ CH₂Ph

80 H (CH₂)₃CH₃

81 CONH₂ (CH₂)₃CH₃

82 H CH₂Ph

83 CONH₂ CH₂Ph

84 H CH₂Ph

85 CONH₂ CH₂Ph

86 H (CH₂)₃Cl₃

87 CONH₂ (CH₂)₃Cl₃

88 H CH₂Ph

89 CONH₂ CH2Ph [sic]

90 H CH2Ph [sic]

91 CONH₂ CH2Ph [sic]

92 H CH₂Ph

93 CONH₂ CH₂Ph

94 H CH₂Ph

95 CONH₂ CH₂Ph

96 H CH₂Ph

97 CONH₂ CH₂Ph

98 H (CH₂)₃CH₃

99 CONH₂ (CH₂)₃CH₃

100 H CH₂Ph

101 CONH₂ CH₂Ph

102 H (CH₂)₃CH₃

103 CONH₂ (CH₂)₃CH₃

104 H CH₂Ph

105 CONH₂ CH₂Ph

106 H

107 CONH₂ (CH₂)₃CH₃

108 H CH₂Ph

109 CONH₂ CH₂Ph

110 H (CH₂)₃CH₃

111 CONH₂ (CH₂)₃CH₃

112 H CH₂Ph

113 CONH₂ CH₂Ph

114 H (CH₂)₃Cl₃

115 CONH₂ (CH₂)₃Cl₃

116 H CH₂Ph

117 CONH₂ CH₂Ph

118 H (CH₂)₃Cl₃

119 CONH₂ (CH₂)₃Cl₃

120 H (CH₂)₃Cl₃

121 CONH₂ (CH₂)₃Cl₃

122 H CH₂Ph

123 CONH₂ CH₂Ph

Example 44N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(piperidin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamide

Ms: m/e=462 (M++1).

Example 60N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(4-ethylpiperazin-1-ylmethyl)-phenyl)-ethen-1-yl)-benzamide

Ms: m/e=524 (M+).

Example 66N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(4-phenylpiperazin-1-ylmethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (D₆-DMSO): δ=2.4 (1H), 2.5 (4H), 2.9 (1H), 3.1 (4H), 3.3 (1H),3.6 (2H), 5.4 (1H), 6.8 (1H), 6.9 (2H) and 7.1-8.0 (18H) ppm.

Example 71N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-diethylaminomethyl)-phenyl)-ethen-1-yl)-nicotinamide

¹H-NMR (D₆-DMSO): δ=1.0 (6H), 2.85 (1H), 3.3 (1H), 3.6 (4H), 5.4 (1H),7.2-8.0 (11H), 8.6 (1H) and 9.2 (1H) ppm.

Example 75N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(N,N-diethylaminomethyl)-phenyl)-ethen-1-yl)-nicotinamide

¹H-NMR (D₆-DMSO): δ=1.0 (9H), 2.5 (4H), 3.5 (2H), 5.2 (1H), 7.3-8.2(12H), 8.7 (1H) and 9.0 (1H) ppm.

Example 77N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(4-methylpiperazin-1-ylmethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (D₆-DMSO): δ=0.9-1.9 (9H), 2.8 (4H), 5.2 (1H), 7.3-8.0 (12H), 8.1(1H) and 8.8 (1H) ppm.

Example 79N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(pyrrolidin-1-ylmethyl)-phenyl)-ethen-1-yl)-nicotinamide

¹H-NMR (CF₃COOD): δ=2.1-2.4 (2H), 3.1-3.4 (3H), 3.6-3.9 (3H), 4.4 (2H),5.2 (1H), 7.0-8.0 (16H) and 8.8 (1H) ppm.

Example 81N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(piperidin-1-ylmethyl)-phenyl)-ethen-1-yl)-nicotinamide

¹H-NMR (D₆-DMSO): δ=0.9-1.9 (15H), 2.9 (2H), 3.2 (2H), 4.3 (2H), 5.2(2H), 7.5-8.1 (11H), 8.8 (1H) and 9.0 (1H) ppm.

Example 83N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(piperidin-1-ylmethyl)-phenyl)-ethen-1-yl)-nicotinamide

¹H-NMR (CF₃COOD): δ=1.6-2.2 (6H); 3.0-3.2 (3H), 3.6-3.8 (2H), 4.3 (2H),6.1 (1H), 7.0-8.0 (14H) and 8.8 (1H) ppm.

Example 85N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(morpholin-1-ylmethyl)-phenyl)-ethen-1-yl)-nicotinamide

¹H-NMR (D₆-DMSO): δ=2.35 (2H), 2.8 (1H), 3.3 (1H), 3.5 (2H), 3.6 (2H),5.4 (1H), 7.0-8.0 (14H), 8.1 (1H), 8.6 (1H) and 9.2 (1H) ppm.

Example 124N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-diethylaminomethyl)-phenyl)-ethen-1-yl)-nicotinamidex dihydrochloride

¹H-NMR (D₆-DMSO): δ=1.1 (6H), 2.9 (1H), 3.1 (4H), 3.3 (1H), 4.3 (2H),5.5 (1H), 7.2-8.0 (13H), 8.7 (2H), 9.3 (1H) and 10.8 (broad) ppm.

Example 125N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-dimethylaminomethyl)-phenyl)-ethen-1-yl)-nicotinamidex dihydrochloride

¹H-NMR (D₆-DMSO): δ=2.7 (6H), 2.9 (1H), 3.2 (1H), 4.3 (2H), 5.5 (1H),7.2-8.0 (16H) and 8.6 (1H) ppm.

Example 126N-(Butan-1-al-2-yl)-2-(E-2-(4-(N,N-dimethylaminomethyl)phenyl)-ethen-1-yl)-5-methoxybenzamide

¹H-NMR (CDCL₃) [sic]: δ=1.0 (3H), 1.8 (1H), 2.1 (1H), 3.0 (6H), 3.8(3H), 4.6 (2H), 4.8 (1H), 6.4 (1H), 6.8-7.2 (3H), 7.3-7.8 (6H) and 9.7(1H) ppm.

Example 1272-(E-2-(4-(N,N-Dimethylaminomethyl)phenyl)-ethen-1-yl)-5-methoxy-N-(pentan-1-al-2-1)-benzamide[sic] Example 128N-(3-Cyclohexyl-propan-al-2-yl)-2-(E-2-(4-(piperidin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=1.0 (2H), 1.2 (3H), 1.5 (4H), 1.7 (8H), 1.8(2H), 2.5 (3H), 3.6 (2H), 4.9 (1H), 6.2 (1H), 7.1 (1H), 7.3 (1H), 7.4(2H), 7.5 (5H), 7.7 (1H) and 9.6 (1H) ppm.

Example 129N-(4-Methylpentan-1-al-2-yl)-2-(E-2-(4-(piperidin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=0.9 (3H), 1.0 (3H), 1.4 (3H), 1.6 (6H), 1.8(2H), 2.4 (2H), 3.5 (2H), 4.8 (1H), 6.2 (1H), 7.0 (1H), 7.2-7.6 (8H),7.7 (1H) and 9.7 (1H) ppm.

Example 130N-(Pentan-1-al-2-yl)-2(E-2-(4-(piperidin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=0.9 (3H), 1.4-1.6 (10H), 2.4 (4H), 3.4 (2H), 4.8(1H), 6.3 (1H), 7.0 (1H), 7.2-7.6 (7H), 7.7 (1H) and 9.7 (1H) ppm.

Example 1312-(E-2-(4-(N,N-Dimethylamino-methyl)phenyl)-ethen-1-yl)-N-(3-phenyl-propan-1-al-2-yl)-5-methoxy-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=2.3 (6H), 3.3 (2H), 3.6 (2H), 3.8 (3H), 4.9(1H), 6.5 (1H), 7.0-7.4 (13H), 8.5 (1H) and 9.7 (1H) ppm.

Example 132N-(3-(3-Indolyl)-propan-1-al-2-yl)-2-(E-2-(4-(piperidin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=1.4 (2H), 1.6 (4H), 2.4 (4H), 3.4 (2H), 3.5(2H), 5.1 (1H), 6.4 (1H), 6.9 (2H), 7.1-7.5 (11H), 7.6 (2H), 8.1 (1H)and 9.8 (1H) ppm.

Example 133N-(3-(4-Imidazolyl)-propan-1-al-2-yl)-2-(E-2-(4-(piperidin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (D₆-DMSO): δ=1.4 (2H), 1.6 (4H), 2.4 (4H), 3.4 (2H), 4.1 (2H),4.6 (1H), 7.1 (1H), 7.2-7.7 (11H), 7.8 (1H), 8.9 (1H) and 9.7 (1H) ppm.

Example 134N-(3-Cyclohexyl-propan-1-al-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (CDCl₃): δ=0.8-1.7 (11H), 1.8 (2H), 2.8 (4H), 3.8 (6H), 4.9 (1H),6.4 (1H), 7.0 (1H); 7.2-7.6 (8H), 7.7 (1H) and 9.6 (1H) ppm.

Example 135N-(4-Methyl-pentan-1-al-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=1.0 (6H), 1.5 (2H), 2.1 (1H), 2.8 (4H), 3.7-3.9(6H), 4.8 (1H), 6.3 (1H), 7.0 (1H), 7.2-7.8 (9H) and 9.7 (1H) ppm.

Example 1362-(E-2-(4-(Morpholin-1-yl-methyl)phenyl)-ethen-1-yl)-N-(pentan-1-al-2-yl)-benzamide

¹H-NMR (CDCL₃) [sic]: δ=1.0 (3H), 1.5 (2H), 1.7 (2H), 2.4 (4H), 3.4(2H), 3.7 (4H), 4.9 (1H), 6.3 (1H), 7.0 (1H), 7.2-7.6 (8H), 7.7 (1H) and9.7 (1H) ppm.

Example 137N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(pyrrolidon-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamidex methanesulfonic acid

¹H-NMR (D₆-DMSO): δ=1.8-2.1 (2H), 2.3 (3H), 2.6-2.9 (2H), 3.1-3.3 (2H),4.25 (2H), 4.8 (1H), 7.0-8.0 (17H) and 9.8 (1H) ppm.

Example 138N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamidex methanesulfonic acid

¹H-NMR (D₆-DMSO): δ=2.3 (3H), 2.8 (1H), 3.2 (1H), 3.7 (2H), 3.9 (2H),4.2 (1H), 5.3 (1H), 7.0-7.7 (14H), 7.9 (2H), 8.1 (1H), 9.0 (1H) and 9.8(broad) ppm.

Example 139N-(3-Imidazolyl-propan-1-al-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR CDCl₃): δ=2.4-2.8 (6H), 3.5 (2H), 3.7 (4H), 4.8 (1H), 6.6-7.6(13H), 7.9 (1H) and 9.6 (1H) ppm.

Example 140N-(3-Indolyl-propan-1-al-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (D₆-DMSO): δ=2.4 (6H), 3.4 (4H), 3.6 (4H), 4.7 (1H), 6.9-7.9(16H), 8.1 (1H) and 9.7 (1H) ppm.

Example 1412-(E-2-(4-(N,N-Dimethylamino-methyl)phenyl)-ethen-1-yl)-N-(3-indolyl-propan-1-al-2-yl)-benzamide[sic]

¹H-NMR (CDCL₃) [sic]: δ=2.3 (6H), 3.4 (4H), 5.1 (1H), 6.4 (1H), 6.9(1H), 7.0-7.5 (13H), 7.6 (2H) and 9.6 (1H) ppm.

Example 142N-(1-Carbamoyl-1-oxo-propan-2-yl)-2-(E-2-(4-(N,N-dimethylamino-methyl)-phenyl)-ethen-1-yl)-benzamidehydrochloride

¹H-NMR (D₆-DMSO): δ=1.3 (3H), 2.7 (6H), 4.3 (2H), 5.1 (1H), 7.3-8.0(11H), 8.1 (1H), 9.0 (1H) and 11.2 (broad) ppm.

Example 143N-(1-Carbamoyl-1-oxo-propan-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)-phenyl)-ethen-1-yl)-nicotinamidedihydrochloride

¹H-NMR (D₆-DMSO): δ=1.4 (3H), 3.1 (2H), 3.2 (2H), 3.8-4.0 (4H), 4.4(2H), 5.2 (1H), 7.5-8.2 (10H), 8.7 (1H), 9.2 (1H) and 11.6 (broad) ppm.

Example 144N-(1-Carbamoyl-1-oxo-propan-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamidehydrochloride

¹H-NMR (D₆-DMSO): δ=1.3 (3H), 3.1 (2H), 3.2 (2H), 3.8 (2H), 3.9 (2H),4.3 (2H), 5.1 (1H), 7.3-8.0 (11H), 8.1 (1H), 8.9 (1H) and 11.4 (broad)ppm.

Example 145N-(1-Carbamoyl-1-oxo-propan-2-yl)-2-(E-2-(4-(4-methylpiperazin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamidedihydrochloride

¹H-NMR (D₆-DMSO): δ=1.35 (3H), 3.0-3.3 (4H), 3.8-4.0 (4H), 4.3 (2H), 5.1(1H), 7.3-8.1 (12H), 8.9 (1H) and 11.5 (broad) ppm.

Example 146N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(4-methylpiperidin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamideExample 147N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(4-methyl-piperidin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamideExample 148N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N-(n-propyl)-N-(2-methyl-propan-1-yl)aminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCL₃) [sic]: δ=0.9 (9H), 1.4 (2H), 1.8 (1H), 2.2 (2H), 2.3(2H), 3.2-3.6 (4H), 5.6 (1H), 5.9 (1H), 6.4 (1H) and 6.8-7.8 (16H) ppm.

Example 149N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(N-(isopropyl)-N-(n-propyl)aminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCL₃) [sic]: δ=0.8 (6H), 1.0 (6H), 1.2-1.4 (4H), 1.7 (1H), 2.0(1H), 2.4 (3H), 3.0 (1H), 3.0-3.2 (1H), 3.6 (2H), 5.4 (1H), 5.8 (1H),6.4 (1H), 6.8 (1H), 7.0 (1H), 7.2-7.4 (7H), 7.6 (1H) and 7.7 (1H) ppm.

Example 150N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(N-(n-propyl)-N-(2-methyl-propan-1-yl)aminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCL₃) [sic]: δ 0.9 (12H), 1.2-1.5 (5H), 1.7 (2H), 2.1 (2H), 2.4(4H), 3.5 (2H), 5.4 (1H), 5.8 (1H), 6.4 (1H), 6.8 (1H), 7.0 (1H) and7.2-7.6 (9H) ppm.

Example 151N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N-(isopropyl)-N-(n-propyl)aminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCl₃): δ 0.8 (3H), 1.2 (6H), 1.5 (2H), 2.4 (2H), 2.9-3.4 (3H),3.6 (2H), 4.6 (1H), 5.8 (1H), 6.4 (1H) and 6.8-7.8 (16H) ppm.

Example 152N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-((3,5dimethylmorpholin-1-yl)methyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (D₆-DMSO): δ 1.0 (6H), 1.7 (2H), 2.8-3.7 (8H), 5.5 (1H), 7.1-7.8(15H), 8.1 (1H) and 9.0 (1H) ppm.

Example 153N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-(dimethoxyeth-1-yl)aminomethyl)-phenyl)-ethen-1-yl)-benzamidehydrochloride

¹H-NMR (D₆-DMSO): δ 3.3-3.8 (10H), 4.5 (2H), 5.5 (1H), 7.0-8.0 (17H) and9.0 (1H) ppm.

Example 1542-(E-2-(4-(4-tert-Butyl-piperidin-1-yl-methyl)-phenyl)-ethen-1-yl)-N-(1-carbamoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide

¹H-NMR (CDCl₃): δ 0.9 (9H), 1.1 (1H), 1.6 (4H), 2.2 (2H), 3.2 (4H), 3.8(2H), 5.6 (1H), 5.8 (1H), 5.9 (1H), 6.4 (1H), 6.9-7.6 (14H) and 7.7 (1H)ppm.

Example 1552-(E-2-(4-(4-tert-Butyl-piperidin-1-yl-methyl)-phenyl)-N-(1-carbamoyl-1-oxo-hexan-2-yl)ethen-1-yl)benzamide

¹H-NMR (CDCl₃): δ 0.9 (9H), 1.2-2.0 (9H), 2.5 (2H), 2.8 (2H), 3.2 (2H),3.3 (1H), 3.5 (2H), 4.1 (2H), 5.4 (1H), 5.9 (1H), 6.4 (1H), 7.0 (1H),7.2 (2H), 7.4-7.6 (7H) and 7.7 (1H) ppm.

Example 1562-(E-2-(4-N,N-n-Butyl-methylaminomethyl)-phenyl)-ethen-1-yl)-N-(1-carbamoyl-1-oxo-hexan-2-yl)-benzamide[sic]

¹H-NMR (D₆-DMSO): δ 0.7 (6H), 1.2 (6H), 1.4 (2H), 2.3 (6H), 2.5 (3H),2.7 (4H), 4.0 (2H), 4.9 (1H), 5.8 (1H), 6.9-7.4 (8H), 7.7 (2H), 7.9 (2H)and 8.7 (1H) ppm.

Example 1572-(E-2-(4-N,N-n-Butyl-methylaminomethyl)-phenyl)-ethen-1-yl)-N-(1-carbamoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide[sic] Example 158N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-(E-2(4-(N,N-n-propyl-methylaminomethyl)-phenyl)-ethen-1-yl)-benzamide[sic] Example 159N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2(4-(N,N-(2-methyl-but-2-yl)-methylaminomethyl-phenyl)-ethen-1-yl)-benzamide[sic] Example 160N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(N,N-(2-methyl-but-2-yl)-methylaminomethyl)-phenyl)-ethen-1-yl)-benzamide[sic] Example 161N-(1-Carbamoyl-1-oxo-hexan-2-yl)-2-(E-2-(4-(N,N-n-propyl-methylaminomethyl)-phenyl)-ethen-1-yl)-benzamide[sic]

¹H-NMR (D₆-DMSO): δ 0.8 (6H), 1.3 (4H), 1.7 (2H), 2.4-2.6 (5H), 2.8(2H), 4.0-4.2 (2H), 5.1 (1H), 7.1-7.6 (9H), 7.8 (2H), 8.1 (1H) and 8.8(1H) ppm.

Example 1622-(E-2-(4-(N,N-n-Butyl-ethylaminomethyl)-phenyl)-ethen-1-yl)-N-(1-carbamoyl-1-oxo-3-phenyl-propan-2-yl)-benzamide[sic] Example 163N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(hexahydroazepin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamideExample 164N-(1-Carbamoyl-1-oxo-n-hexan-2-yl)-2-(E-2-(4-(hexahydroazepin-1-yl-methyl-phenyl)-ethen-1-yl)-benzamideExample 165N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-diethylaminomethyl)-phenyl)-ethen-1-yl)-benzamidex methanesulfonic acid

¹H-NMR (D₆-DMSO): δ 1.2 (6H), 2.3 (3H), 2.9 (1H), 3.1 (4H), 3.2 (1H),4.3 (2H), 5.4 (1H), 7.2-8.0 (15H), 8.2 (1H), 8.9 (1H) and 9.4 (1H) ppm.

Example 1662-(E-2-(4-(N,N-n-Butyl-ethylaminomethyl)-phenyl)-ethen-1-yl)-N-(1-carbamoyl-1-oxo-n-hexan-2-yl)-benzamide[sic]

¹H-NMR (D₆-DMSO): δ 0.8 (6H), 1.2-1.5 (7H), 1.5-1.8 (4H), 2.6 (2H), 2.9(2H), 3.0 (2H), 4.3 (2H), 5.2 (1H), 7.2-7.7 (9H), 7.8 (2H), 8.1 (1H) and8.9 (1H) ppm.

Example 167N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-diethylaminomethyl)-phenyl)-ethen-1-yl)-4-methyl-benzamidehydrochloride

MS: m/e=469 (M+).

Example 168N-(1-Carbamoyl-1-oxo-n-hexan-2-yl)-2-(E-2-(4-(N-ethyl-N-isopropylaminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCl₃): δ 0.5 (9H), 1.0 (3H), 1.3 (3H), 1.8 (2H), 2.1 (2H), 2.4(4H), 3.5 (2H), 5.4 (1H), 5.7 (1H), 6.4 (1H), 6.8 (1H), 7.1 (1H),7.2-7.6 (8H) and 7.7 (1H) ppm.

Example 169N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N-ethyl-N-isopropylaminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCl₃): δ 0.9 (6H), 1.0 (3H), 1.8 (1H), 2.2 (2H), 2.4 (2H), 3.1(2H), 3.6 (2H), 5.7 (1H), 6.4 (1H), 6.9-7.5 (16H) and 7.7 (1H) ppm.

Example 170N-(1-Carbamoyl-1-oxo-n-hexan-2-yl)-2-(E-2-(4-(N-cyclohexyl-N-methylaminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCl₃): d 0.8 (3H), 1.1-1.5 (9H), 1.6-2.1 (6H), 2.2 (3H), 2.5(2H), 3.6 (2H), 5.4 (1H), 5.8 (1H), 6.4 (1H), 6.8 (1H), 7.0 (1H),7.2-7.6 (8H) and 7.8 (1H) ppm.

Example 171N-(1-Carbamoyl-1-oxo-n-hexan-2-yl)-2-(E-2-(4-(N-methylpiperazin-1-yl-methyl)-phenyl)-ethen-1-yl)-nicotinamidedihydrochloride

¹H-NMR (D₆DMSO): δ 0.9-1.9 (10H), 2.8 (2H), 4.4 (2H), 5.2 (1H), 7.4-8.2(13H), 8.7 (1H) and 9.1 (1H) ppm.

Example 172N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(methyl-piperazin-1-yl-methyl)-phenyl)-ethen-1-yl)-nicotinamidedihydrochloride

MS: m/e=511 (M+).

Example 173N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N-cyclohexyl-N-methylaminomethyl)-phenyl)-ethen-1-yl)-benzamide

¹H-NMR (CDCl₃): δ 0.9 (2H), 1.1-1.4 (7H), 1.6 (1H), 1.8 (2H), 2.1 (2H),2.4 (3H), 3.9 (2H), 5.5 (1H), 5.9 (1H), 6.4 (1H) and 6.8-7.8 (16H) ppm.

Example 174N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)-phenyl)-ethen-1-yl)-nicotinamidedihydrochloride

¹H-NMR (D₆DMSO): δ 2.8 (1H), 3.0-3.4 (5H), 3.8-4.0 (4H), 4.4 (2H), 5.5(1H), 7.0-8.0 (13H), 8.2 (1H), 8.7 (1H), 8.7 (1H), 9.2 (1H) and 11.8(broad) ppm.

Example 175N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(N,N-dimethylamino-methyl)-phenyl-ethen-1-yl)-nicotinamidedihydrochloride

¹H-NMR (D₆DMSO): δ 1.3 (6H), 2.9 (1H), 3.0-3.2 (4H), 3.3 (1H), 4.3 (2H),5.4 (1H), 7.2-8.0 (13H), 8.2 (1H), 8.7 (1H), 9.2 (1H) and 10.6 (broad)ppm.

Example 176N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(1,2,5,6-tetrahydropyridin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamide

MS: m/e=493 (M+).

Example 177N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-3-chloro-2-(E-2-(4-(N,N-dimethylamino-methyl)-phenyl)-ethen-1-yl)-benzamideExample 178N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(E-2-(4-(4-methyl-piperazin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamidex 2 methanesulfonic acid

¹H-NMR (D₆-DMSO): δ 2.4 (12H), 2.8-3.7 (11H), 4.5 (2H), 5.4 (1H),7.2-8.0 (18H), 8.2 (1H) and 9.0 (1H) ppm.

Example 179N-(1-Carbamoyl-1-oxo-n-butan-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)-phenyl)-ethen-1-yl-benzamidehydrochloride

¹H-NMR (D6-DMSO): δ 1.0 (3H), 1.6 (1H), 1.9 (1H), 3.0-3.4 (4H), 3.7-4.0(4H), 4.3 (2H), 5.2 (1H), 7.2-8.2 (12H), 8.9 (1H) and 11.8 (broad) ppm.

Example 180N-(1-Carbamoyl-3-methyl-1-oxo-n-butan-2-yl)-2-(E-2-(4-(4-methyl-piperazin-1-yl-methyl)-phenyl)-ethen-1-yl-benzamidex 2 methanesulfonic acid

¹H-NMR (D₆-DMSO): δ 0.9-1.1 (6H), 2.3 (3H), 2.8 (3H), 3.0-3.8 (8H), 3.9(2H), 5.1 (1H), 7.0-8.1 (12H) and 8.8 (1H) ppm.

Example 181N-(1-Carbamoyl-3-methyl-1-oxo-n-butan-2-yl)-2-(E-2-(4-(morpholin-1-yl-methyl)-phenyl)-ethen-1-yl)-benzamidex methanesulfonic acid

¹H-NMR (D₆-DMSO): δ 0.9-1.1 (6H), 2.3 (4H), 3.0-3.5 (4H), 3.6-4.0 (4H),4.4 (2H), 5.2 (1H), 7.2-8.1 (12H), 8.8 (1H) and 9.8 (broad) ppm.

Example 182N-(1-Carbamoyl-1-oxo-n-butan-2-yl)-2-(E-2-(4-(4-methylpiperazin-1-yl-methyl)-phenyl)-ethen-1-yl-benzamidedihydrochloride

¹H-NMR (D₆-DMSO): δ 1.0 (3H), 1.6 (1H), 1.9 (1H), 2.8 (3H), 3.3-3.8(10H), 5.1 (1H), 7.3-8.1 (12H), and 8.8 (1H) ppm.

Example 183N-(1-Carbamoyl-1-oxo-n-hexan-2-(4(piperidin-1-yl-methyl)-phenyl)-benzamide[sic] Example 184N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(4-(piperidin-1-yl-methyl)-phenyl)-benzamideExample 185N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(N-methyl-tetrahydroisoquinolin-7-yl)oxy-nicotinamide

Ms: m/e=458 (M+).

Example 186N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(N-methyl-tetrahydroisoquinolin-7-yl)oxy-benzamide

Ms: m/e=458 (M+).

Example 187N-(3-Phenyl-propan-1-al-2-yl)-2-(4-(piperidin-1-yl-methyl)-benzyloxy)-nicotinamide[sic] Example 1882-(4-(N,N-Dimethylaminomethyl)-benzyloxy)-N-(3-phenyl-propan-1-al-2-yl)nicotinamide[sic] Example 189N-(3-Phenyl-propan-1-al-2-yl)-2-(4-(4-methylpiperazin-1-yl-methyl)-benzyloxy)-nicotinamideExample 190N-(1-Carbamoyl-1-oxo-3-phenyl-propan-2-yl)-2-(4-(2-(N,N,dimethylamino)-eth-1-yl))-phenyloxy-nicotinamidehxydrochloride [sic]

We claim:
 1. An amide of the formula I

and its tautomeric forms, enantiomeric and diastereomeric forms, E and Zforms, and physiologically tolerated salts, in which the variables havethe following meanings: A —(CH₂)_(p)—R¹, where R¹ is pyrrolidine,morpholine, hexahydroazepine

 piperidine, or —NR⁵R⁶ where the cyclic amines are optionally besubstituted by one or two R¹⁵ radicals, and R¹⁵ hydrogen, C₁-C₆-alkyl,O—C₁-C₆-alkyl or phenyl, and R⁵, R⁶ and R⁷ are, independently of oneanother, hydrogen, C₁-C₄-alkyl, cyclohexyl, cyclopentyl, CH₂Ph, Ph, orCH₂CH₂Ph, where the phenyl rings are optionally substituted by R⁶, and pcan be 1 or 2 and B is phenyl, pyridyl, pyrazyl, pyrimidyl or pyridazylwhich are optionally substituted by up to 2 R⁸ radicals, and A and Btogether are also

 and R¹⁶ is hyrogen, C₁-C₆-alkyl or (CH₂)₁₋₄-phenyl, where the phenylring is optionally substituted by a maximum of 2 R⁶ radicals, and D canbe a bond, —(CH₂)₀₋₂—O—(CH₂)₀₋₂, —(CH₂)_(m)—, —CH═CH—, —C≡C, and R² ischlorine, bromine, flourine, C₁-C₆-alkyl, NHCO—C₁-C₄-alkyl,NHSO₂—C₁-C₄-alkyl, NO₂, —O—C₁-C₄-alkyl or NH₂, and R³ is —C₁-C₆-alkyl,branched or unbranched, which is optionally substituted with a SCH₃radical, phenyl ring, imidazolyl ring, indolyl ring, cyclopentyl ring,cycloheptyl ring or cyclohexyl ring which is in turn substituted by amaximum of two R⁸ radicals, where R⁸ is hydrogen, C₁-C₄-alkyl, branchedor unbranched, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN,COOH, COO—C₁-C₄-alkyl, NHCO—C₁-C₄-alkyl, —NHSO₂—C₁-C₄-alkyl or—SO₂—C₁-C₄-alkyl; and Y is phenyl and R⁴ is hydrogen, COOR⁹ or CO—Z inwhich Z is NR¹⁰R¹¹,

R⁹ is hydrogen or C₁-C₆-alkyl, linear or branched, which is optionallysubstituted by a phenyl ring which is optionally substituted by one ortwo R¹² radicals, and R¹⁰ is hydrogen; C₁-C₆-alkyl; linear or branched,which is optionally substituted by a phenyl ring which is optionallysubstituted by one or two R¹² radicals,

R¹¹ is hydrogen or C₁-C₆ alkyl, branched or unbranched, which isoptionally substituted by a phenyl ring which is optionally substitutedby an R⁹ radical, and R¹² can be is hydrogen, C₁-C₄-alkyl, branched orunbranched, —O—C₁-C₄-alkyl, OH, Cl, F, Br, I, CF₃, NO₂, NH₂, CN, COOH,COO—C₁-C₄-alkyl, —NHCO—C₁-C₄-alkyl, —NHCO-phenyl, —NHSO₂—C₁-C₄-alkyl,NHSO₂-phenyl, —SO₂—C₁-C₄-alkyl or —SO₂-phenyl, and R¹³ is hydrogen orC₁-C₆-alkyl, linear or branched, which is optionally substituted by aphenyl ring which is optionally substituted by one or two R¹² radicals,and R¹⁴ is hydrogen or C₁-C₆-alkyl, linear or branched, which isoptionally substituted by a phenyl ring which is optionally substitutedby one or two R¹² radicals, and n is a number 0, 1 or 2, and m and qare, independently of one another, a number 0, 1, 2, 3 or
 4. 2. An amideof the formula I as claimed in claim 1 where A is —CH₂—R¹; B is phenyl;D is —CH═CH—; R² is hydrogen; R³ is benzyl, CH₂—CH₃, CH₂—CH₂—CH₃,CH₂CH₂CH₂CH₃, or CH₂CH₂CH₂CH₂CH₃; Y is phenyl R⁴ is CO—NH₂ and all theremaining variables have the same meaning as in claim
 1. 3. An amide ofthe formula I as claimed in claim 1, where A is —CH₂—R¹; B is phenyl; Dis —CH═CH—; R² is hydrogen; R³ is benzyl, CH₂—CH₃, CH₂—CH₂—CH₃,CH₂CH₂CH₂CH₃; or CH₂CH₂CH₂CH₂CH₃; Y is phenyl; R⁴ is hydrogen and allthe remaining variables have the same meaning as in claim
 1. 4. Apharmaceutical preparation composition for oral, parenteral orintraperitonal use, comprising at least one amide claim 1 per singledose, and conventional pharmaceutical ancillary substances.
 5. A methodof treating a patient having a condition treatable by inhibitingcysteine proteases comprising administering to said patient an effectiveamount of an amide of claim
 1. 6. The method of claim 5 wherein thecysteine proteases are calpains or cathepsins.
 7. The method of claim 5wherein the condition is a disease in which elevated calpain activitiesoccur.
 8. A method of treating a patient having a neurodegenerativedisorder or neuronal damage comprising administering to said patient aneffective amount of an amide of claim
 1. 9. The method of claim 8wherein the neurodegenerative disorders or neuronal damage is induced byischemia, trauma or massive bleeding.
 10. The method of claim 8 whereinthe neurodegenerative disorder or neuronal damage is stroke orcraniocerebral trauma.
 11. The method of claim 8 wherein theneurodegenerative disorder or neuronal damage is Alzheimer's disease orHuntington's disease.
 12. The method of claim 8 wherein theneurodegenerative disorder or neuronal damage is epilepsy.
 13. A methodof treating a patient having damage to the heart after cardiacischemias, damage due to reperfusion after vascular occlusions, damageto the kidneys after renal ischemias, skeletal muscle damage, musculardystrophies, damage produced by proliferation of smooth muscle cells,coronary vasospasm, cerebral vasospasm, cataracts of the eyes orrestenosis of blood vessels after angioplasty, comprising administeringto said patient an effective amount of an amide of claim
 1. 14. A methodof treating a patient having tumors or metastasis thereof, comprisingadministering to said patient an effective amount of an amide ofclaim
 1. 15. A method of treating a patient having disorders in whichelevated interleukin-1 levels occur, comprising administering to saidpatient an effective amount of an amide of claim
 1. 16. A method oftreating a patient having immunological disorders, comprisingadministering to said patient an effective amount of an amide ofclaim
 1. 17. The method of claim 6 wherein the calpains are calpain I,calpain II, cathepsin B or cathepsin L, comprising administering to saidpatient an effective amount of an amide of claim
 1. 18. The method ofclaim 16 wherein the immunological disorder is inflammation or arheumatic disorder.